Molecular Dynamics Investigations of Dienolate [4 + 2] Reactions.

We report quantum mechanics calculations and quasiclassical trajectory simulations of [4 + 2] reactions using three common dienolate substrates: siloxy dienes, Li dienolates, and conjugated Pd enolates. Asynchronous transition structures and unequal bond formation were invariably found, with average time gaps of developing bonds ranging from 26.5 to >251.0 fs. The results display a spectrum of dynamically concerted and stepwise [4 + 2] reactions, offering insights into the origin of the stereochemical outcomes of such reactions.

Minimizing higher-order aggregation maximizes iron mobilization by small molecules.

The natural product hinokitiol mobilizes iron across lipid bilayers at low concentrations and restores hemoglobinization in iron transporter protein-deficient systems. But hinokitiol fails to similarly mobilize iron at higher concentrations, limiting its uses in chemical biology and medicine. Here we show that at higher concentrations, hinokitiol3:Fe(III) complexes form large, higher-order aggregates, leading to loss of transmembrane iron mobilization. Guided by this understanding and systematic structure-function studies enabled by modular synthesis, we identified FeM-1269, which minimally aggregates and dose-dependently mobilizes iron across lipid bilayers even at very high concentrations. In contrast to hinokitiol, FeM-1269 is also well-tolerated in animals at high doses for extended periods of time. In a mouse model of anemia of inflammation, FeM-1269 increases serum iron, transferrin saturation, hemoglobin and hematocrit. This rationally developed iron-mobilizing small molecule has enhanced potential as a molecular prosthetic for understanding and potentially treating iron transporter deficiencies.

Nickel-Catalyzed Enantioconvergent and Diastereoselective Allenylation of Alkyl Electrophiles: Simultaneous Control of Central and Axial Chirality.

In recent years, remarkable progress has been described in the development of methods that simultaneously control vicinal stereochemistry, wherein both stereochemical elements are central chirality; in contrast, methods that control central and axial chirality are comparatively rare. Herein we report that a chiral nickel catalyst achieves the enantioconvergent and diastereoselective coupling of racemic secondary alkyl electrophiles with prochiral 1,3-enynes (in the presence of a hydrosilane) to generate chiral tetrasubstituted allenes that bear an adjacent stereogenic center. A carbon-carbon and a carbon-hydrogen bond are formed in this process, which provides good stereoselectivity and is compatible with an array of functional groups.

Divergent Catalysis: Catalytic Asymmetric [4+2] Cycloaddition of Palladium Enolates.

An asymmetric decarboxylative [4+2] cycloaddition from a catalytically generated chiral Pd enolate was developed, forging four contiguous stereocenters in a single transformation. This was achieved through a strategy termed divergent catalysis, wherein departure from a known catalytic cycle enables novel reactivity of a targeted intermediate prior to re-entry into the original cycle. Mechanistic studies including quantum mechanics calculations, Eyring analysis, and KIE studies offer insight into the reaction mechanism.

A Mild Method for Making MIDA Boronates.

We disclose that a predried form of methyliminodiacetic acid (MIDA), MIDA anhydride, acts as both a source of the MIDA ligand and an in situ desiccant to enable a mild and simple MIDA boronate synthesis procedure. This method expands the range of sensitive boronic acids that can be converted into their MIDA boronate counterparts. Further utilizing unique properties of MIDA boronates, we have developed a MIDA Boronate Maker Kit which enables the direct preparation and purification of MIDA boronates from boronic acids using only heating and centrifuge equipment that is widely available in laboratories that do not specialize in organic synthesis.